The connective tissue of vascular walls is formed from two principal types of protein. Collagen, in general, the principal proteinaceous component of connective tissue, constitutes the structural element imparting strength to the tissue. However, where the demand for elasticity is great as in the aortic arch and descending thoracic aorta, there is twice as much elastin as collagen. In the vascular wall, and particularly in the internal elastic lamina thereof, collagen is associated with natural elastic fibers formed from a different type of protein, known as tropoelastin. In the relaxed vascular wall, collagen fibers tend to be folded or crimped, and the elastic fibers are in a retracted state. Upon distention or stretching, the elastic fibers become stretched, and, before their extension limit is approached, the collagen fibers come into tension to bear the load. As the load diminishes, the elastic fibers draw the wall back to its original dimension and the collagen fibers back into a folded state.
The above can also be demonstrated experimentally, for if the collagen component of an intact ligament is removed in vitro by the enzyme collagenase, the resultant stress-strain relationship clearly indicates that the elastic component, elastin, is principally responsible for the initial high yield response of the intact ligament. Conversely, removal of elastin by the enzyme elastase leaves collagen which is observed to be responsible for only the final portion of the response of the intact ligament. See Introductory Biophysics, F. R. Hallett et al. (Halsted Press, 1977).
Presently available synthetic vascular materials, such as Dacron, are quite different from natural connective tissue in that the synthetic weave can be viewed as providing the structural analog of folded collagen, but there is no true elastomeric component therein.
The central portion of the elastic fibers of vascular wall, skin, lung and ligament is derived from a single protein called tropoelastin. Elastin, the actual elastomeric component of biological elastic fibers, is composed of a single protein and is formed from the cross-linking of the lysine residues of tropoelastin. The sequence of elastin can be described as a serial alignment of alanine-rich, lysine-containing cross-linking sequences alternating with glycine-rich hydrophobic sequences. More than 80% of the elastin sequence is known, and it has been shown that vascular wall tropoelastin contains a repeat hexapeptide (Ala-Pro-Gly-Val-Gly-Val).sub.n, a repeat pentapeptide (Val-Pro-Gly-Val-Gly).sub.n, and a repeat tetrapeptide (Val-Pro-Gly-Gly).sub.n where Ala, Pro, Val and Gly, respectively, represent alanine, proline, valine, and glycine amino acid residues. These residues can also be represented, respectively, as A, P, and G, inasmuch as amino acids can be referred to either by standard three-letter or one-letter abbreviations. See, for example, Organic Chemistry of Biological Compounds, pages 56-58 (Prentice-Hall, 1971). Further, in this application, all peptide representations conform to the standard practice of writing the NH.sub.2 -terminal amino acid residue on the left of the formula and the CO.sub.2 H-terminal amino acid residue on the right. Furthermore, unless otherwise specified all amino acids are of the L-configuration, with the exception of Glycine, which is optically inactive.
The nature of the amino acid sequence in the vicinity of the tropoelastin cross-links is also known. Moreover, a high polymer of the hexapeptide has been synthesized, and found to form cellophane-like sheets. In view of this, and its irreversible association on raising the temperature in water, the hexapeptide is, therefore, thought to provide a structural role in the natural material. On the other hand, synthetic high polymers of the pentapeptide and of the tetrapeptide have been found to be elastomeric when cross-linked and have the potential to contribute to the functional role of the elastic fiber. In fact, the chemically cross-linked polypentapeptide can, depending upon its water content and degree of crosslinking, exhibit the same elastic modulus as native aortic elastin.
More recently, a synthetic polypentapepide based on the pentapeptide sequence disclosed above was disclosed and claimed in U.S. Pat. No. 4,187,852 to Urry and Okamoto. Furthermore, a composite bioelastic material based on an elastic polypentapeptide or polytetrapeptide and a strength-giving fiber was disclosed and claimed in U.S. Pat. No. 4,474,851 to Urry. Additionally, a bioelastic material having an increased modulus of elasticity formed by replacing the third amino acid in a polypentapeptide with an amino acid of opposite chirality was disclosed and claimed in U.S. Pat. No. 4,500,700 to Urry and to an enzymatically cross-linked polypeptide as disclosed in and claimed in U.S. Pat. No. 4,589,882. Finally, it is also noted that at present, Ser. No. 533,670, directed to a chemotactic peptide and Ser. No. 793,225, directed to a second chemotactic peptide are both pending. Also pending is Ser. No. 853,212, directed to a segmented polypeptide bioelastomer for the modulation of elastic modulus.
At present, there is a tremendous demand for new synthetic vascular materials and prostheses. Hence, there is a consequent demand for new bioelastic materials based on the above-described polypentapeptide and polytetrapeptide repeating sequences which have desirable, but modified chemical and biological characteristics. This demand is, perhaps, due to the ubiquitous nature of elastin in the human body and the implications thereof. For example, in the extracellular matrix of the vascular wall, the elastin fiber is a primary site of lipid deposition contributing to the gruel of atherosclerosis. Further, in pulmonary emphysema, elastin fibers are disrupted and rendered dysfunctional. Additionally, it can be noted that there are many disease states involving elastin fibers and dysfunctions thereof, for example, the heritable disorders such as pseudoxanthoma elasticum, cutis laxa, endocardial fibroelastosis, and the Buscke-Ollendorf, Ehlers-Danlos, Menkes, and Marfans syndromes. Furthermore, elastin fiber dysfunction is also implicated in the acquired diseases: actinic elastosis, isolated elastomas, elastofibroma dorsi and elastosis perforans serpiginosa. Even from a purely cosmetic standpoint, it is known that solar elastosis of the dermis contributes to the wrinkles of age, and underlying the wrinkles, the elastin fibers are found to be ruptured. Clearly, the development of new synthetic polypentapeptide and polytetrapeptide elastomers would provide, for the first time, versatile substitutes for damaged natural elastin fibers as well as new methods for treating these various diseases.
However, until recently, little has been known about the elastic properties of the bioelastomeric polytetrapeptides and polypentapeptides. Thus, the rational design of specific bioelastomers for particular structural purposes has been extremely limited. For example, up until the present, it has not been possible to vary the temperature range over which would occur the elastomeric force development of synthetic bioelastomers. It would seem that such control would be imperative in order to rationally design a suitable bioelastomeric material for a given purpose. For example, in order to design a thermomechanical transducer for a predetermined temperature, it is necessary to provide materials which development elastomeric force within different temperature ranges.
It is difficult to underestimate the importance of selecting the right material for a particular biological or industrial function. For example, in Technology Review, Nov./Dec. 1984 (Edited at MIT), it was noted that a major obstacle to the development of a reliable artificial heart, as well as prosthetic devices generally, was the lack of suitable synthetic biomaterials. In the case of the artificial heart, it was found that calcium was deposited therein to an unacceptable extent, among other problems. Quite appropriately, Bronowski has noted in his Olympian work the Ascent of Man, that:
In effect the modern problem is no longer to design a structure from the materials but to design materials for a structure. PA1 I is a peptide-forming residue of L-isoleucine; PA1 P is a peptide-forming residue of L-proline; PA1 G is a peptide-forming residue of glycine; PA1 V is a peptide-forming residue of L-valine; and
However, before bioelastic materials can be rationally designed for particular biological purposes requiring variable elasticity, it will be necessary to provide a means for rationally controlling the elastomeric force development of the bioelastomer. Thus, it would be extremely desirable to provide a means for controlling the elastomeric force development of the bioelastomers as a function of temperature. This would greatly broaden the variety of environments in which such materials could function. At present, no such control is possible.
Accordingly, in general, a need clearly continues to exist for bioelastic materials based on polypentapeptide and polytetrapeptide repeating sequences which exhibit desirable chemical and biological characteristics. In particular, a need continues to exist for such bioelastic materials, the elastomeric force development of which can be controlled and varied as a function of temperature.